1. Intranasal Medications in clinical practice

2. Transmucosal medication delivery
Is this really a novel idea?
Commercially available transmucosal drugs:
Actiq oral (transmucosal fentanyl lollipop)
Nitroglycerin – Sublingual.
Stadol (butorphanol) - Intranasal opiate.
Fentora - Transmucosal fentanyl tablet
DDAVP - Intranasal delivery route.
Migraine medications – Migranol (DHE), etc.
Influenza Vaccine - Intranasal system is available.
Active area of pharmacology research

3. Transmucosal Drug Delivery
Many IV medications, including analgesics and sedatives, can be delivered transmucosally, though not currently available for that indication commercially:
Large literature base to support their use.
Generic drugs are available, cutting costs significantly.

4. Why Intranasal (IN) medications?
This delivery route has several advantages:
Its easy and convenient
Almost everyone has a nose
The nose is a very easy access point for medication delivery - even easier to access than IM or IV sites, much easier than rectal delivery
No special training is required to deliver the medication
No shots are needed
Painless
Low risk
It eliminates any risk of a needle stick to the medical provider

5. Intranasal Medication Administration
Needleless: Intranasal Medication administration offers a truly “Needleless” solution to drug delivery.
Superior: Intranasal medication administration generally results in superior drug delivery to the blood stream compared to other transmucosal routes.
The remainder of this discussion will surround the topic of intranasal drug delivery issues.

6. Lecture Outline
Part 1:
Discuss the concept of “Off-label medication”
General principles of intranasal medication delivery
Part 2: Intranasal medications in clinical practice
EMS
Emergency Medicine
Anesthesia
Hospice

7. IN medications: Off-label use
What is “off-label” use
Drugs are approved for specific indications in specific subpopulations by specific route of delivery
All other uses are off label
Common Examples of “off-label” use:
IV lorazepam for status epilepsy in children
Most IV drugs given to children (80%), pregnant women
Most antidotes for drug overdoses
ACLS drugs down an endotracheal tube
H2 blockers for allergies

8. IN medications: Off-label use
Why are so many common uses “off-label”
It costs about $650 million to bring a drug to market for an indication
Once it is on the market, clinicians can use it as they choose for any indication.
Unless there is a HUGE financial incentive to seek another indication, the pharma company will not spend the money to get another indication

9. IN medications: Off-label use
Is it OK to use drugs “off-label”
Yes – in fact is is expected this will occur and this actually helps advance medical care
U.S Supreme court on off-label use: “off-label usage of medical devices is an accepted and necessary corollary of the FDA’s mission”… health care practitioners can “prescribe or administer any legally marketed device to a patient” without limitation or interference.

10. IN medications: Off-label use
Center for drug evaluation and research on off-label use: “Any approved product may be used by a licensed practitioner for uses other than those stated in the product label.”
FDA on off-label use: “Off-label use is a well-established principle that has allowed doctors to discover new and beneficial uses” for previously approved drugs.

11. IN medications: Off-label use
Nice summary on the topic from and Australian committee:
“Routine off-label use (or on-label use) can be justified if there is high-quality evidence supporting efficacy or effectiveness, and sufficient evidence about the medicine’s safety profile to suggest and overall reasonable benefit –risk for a given clinical context”
Conclusion:
Off-label use is acceptable.
Most intranasal drugs are off-label – but that is OK if they provide justifiable benefits.

12. Understanding IN delivery: General principles
First pass metabolism
Nose brain pathway
Lipophilicity
Bioavailability

13. First pass metabolism
Molecules absorbed through the gut, including all oral medications enter the “portal circulation” and are transported to the liver.
Liver enzymes then break down most of these drug molecules and only a small fraction enter the body’s circulation as active drug.
This process is called “First Pass Metabolism.”
POINT: Nasally delivered medications avoid the gut so do not suffer first pass metabolism.

14. First pass metabolism

15. Nose brain pathway
The olfactory mucosa (smelling area in nose) is in direct contact with the brain and CSF.
Medications absorbed across the olfactory mucosa directly enter the CSF.
This area is termed the nose brain pathway and offers a rapid, direct route for drug delivery to the brain.
Olfactory mucosa, nerve
Brain
CSF
Highly vascular nasal mucosa

16. Lipophilicity “Lipid Loving” Non-lipophilic molecules
Cellular membranes are composed of layers of lipid material.
Drugs that are lipophilic are easily and rapidly absorbed across the mucous membranes.
Lipophilic molecules
Cell Membrane
Blood stream

17. Bioavailability
How much of the administered medication actually ends up in the blood stream.
Examples:
IV medications are 100% bioavailable.
Most oral medications are about 5%-10% bioavailable due to destruction in the gut and liver.
Nasal medications vary, but when the right drug is delivered in the right way can approach 80%.

18. Bioavailability
Graph demonstrating naloxone serum concentrations when given via IV and IN routes.
Note that IV and IN serum levels are similar after about 5 minutes.

19. Intranasal Medication Administration: Bioavailability
Not all drugs can be delivered via the nasal mucosa.
Factors affecting bioavailability:
Medication characteristics.
Medication volume and concentration.
Nasal mucosal characteristics.
Delivery system characteristics.
Mucosal surface area coverage.
Medication particle size.

20. Intranasal Medication Administration: Factors Affecting Bioavailability
Medication Characteristics:
Drug characteristics that affect bioavailability via the nasal mucosa include:
Molecular size.
Lipophilicity.
pH.
Drug concentration.
Properties of the solution the drug is solubilized within.

21. Volume and concentration:
Intranasal Medication Administration: Factors Affecting Bioavailability
Volume and concentration:
Low volume - High concentration.
Too large a volume or too weak a concentration may lead to failure because the drug cannot be absorbed in high enough quantity to be effective.
Ideal volume for nasal delivery is 1/4 to 1/2 ml per nostril
Volumes over 1 ml per nostril are too large and may result in runoff out of the nostril.

22. Intranasal Medication Administration: Factors Affecting Bioavailability
Nasal mucosal characteristics:
If there is something wrong with the nasal mucosa it may not absorb medications effectively.
Examples:
Vasoconstrictors such as Afrin, cocaine prevent absorption.
Bloody nose, nasal congestion, mucous discharge all prevent mucosal contact of drug.
This might be overcome with suction prior to drug delivery
Destruction of nasal mucosa from surgery or past cocaine abuse – no mucosa to absorb the drug.

23. Intranasal Medication Administration: Factors Affecting Bioavailability
Delivery system characteristics:
Nasal mucosal surface area coverage:
Larger surface area delivery = higher bioavailability.
Particle size:
Particle size microns adheres best to the nasal mucosa.
Smaller particles pass on to the lungs, larger particles form drop and rapidly run-out of the nose.

24. Bioavailability and Particle size
Compared to drops, atomized medication results in:
Larger surface area of coverage.
Smaller liquid particle size allowing thin layer to cover mucosa.
Less run-off out the nasal cavity.

25. Intranasal Medication Administration: Summary
Points:
Nasal drug delivery is convenient and easy, but it may not always be effective.
Nasal drug delivery cannot completely replace the need for injections.
Being aware of the limitations and using the correct equipment and drug concentrations will assist you in predicting times when nasal drug delivery may not be effective.

26. IN drug delivery: Requirements
Appropriate Drug
Known to be bioavailable across the nasal mucosa
Appropriate Concentration
Most concentrated form available
Appropriate patient
Requires treatment
Nasal mucosa healthy, free of obvious severe bleeding, thick mucous, etc

27. IN drug delivery: Conclusions
IN drug delivery is:
Convenient, easy and effective for selected situations
May result in reduced needlestick risk
Can improve and simplify your practice and your patients experience
Will NOT replace the need for injections

28. Nasal Drug Delivery: What Medications?
There are numerous peer reviewed articles on this topic is you search PubMed or other internet sites for specific indications using key words such as “intranasal” and the medication or application you desire.